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Partnering up with Abiraterone Acetate – Potentials for a Harmonious Relationship

Abiraterone acetate has demonstrated benefit across the metastatic prostate cancer spectrum when combined or layered on conventional androgen deprivation therapy. Whether it be metastatic castration-sensitive (mCSPC) or metastatic castration-resistant prostate cancer (mCRPC) in either the pre-or the post-docetaxel setting, the overall survival benefit is certain.1-4 Attempts to advance to the next level with additional agents added to abiraterone acetate, in the first-line mCRPC setting, have been met with mixed results. At this time, other than the continuing foundation of androgen deprivation therapy, there is no therapeutic agent regulatory approved for combination with abiraterone acetate.

The obvious agents to combine with abiraterone acetate were agents already with a proven overall survival benefit for mCRPC. A randomized phase 2 trial of sipuleucel-T with or without abiraterone acetate and prednisone demonstrated no significant decrement on circulating immune biomarkers, however, there were also no promising signs of synergistic or additive effect either.5 The ALLIANCE cooperative group evaluated the combination of abiraterone acetate with enzalutamide, but found no benefit over enzalutamide alone, with evidence of additional toxicity from the combination.6 Unfortunately, adding radium-223 to abiraterone, in the ERA223 trial, demonstrated increased risk of fractures (mostly osteoporotic) over the abiraterone acetate control arm.7 Cabazitaxel has been added to abiraterone acetate with some promise in a randomized, phase 2 trial.8 Additionally, the CHAARTED2 randomized, phase 2 trial is actively accruing the mCRPC patient population, who received prior docetaxel chemotherapy for high volume mCSPC, to abiraterone acetate with or without cabazitaxel (NCT03419234).

Fortunately, there are other therapeutic combinations that still carry promise, but most of these incorporate novel biologic therapies. For instance, the Ipatential150 randomized, phase 3 trial recently demonstrated a radiographic progression-free survival benefit specifically for patients with PTEN loss demonstrated either by immunohistochemistry or next-generation sequencing.9-11 We are still awaiting the overall survival results from that trial to mature. The addition of Olaparib to abiraterone also led to an improvement in radiographic progression-free survival in a biomarker-unselected patient population.12,13 This has led to the randomized phase 3 trial, termed PROpel (NCT03732820), and results are forthcoming.

Most recently, the ACIS trial reported randomized, phase 3 results on the combination of abiraterone acetate with apalutamide versus abiraterone acetate with placebo.14 This was a n=982 patient trial of patients who had not received prior chemotherapy or novel hormonal therapy. There was a statistically significant improvement in the primary endpoint of radiographic progression-free survival, with a median 7.4-month benefit at long-term follow-up(HR 0.70, 95% CI 0.60-0.83). However, overall survival was not improved, with a HR 0.95 (95% CI 0.81-1.11; p=0.498).In addition, other secondary and exploratory endpoints were not able to demonstrate improvement with the apalutamide and abiraterone acetate combination; these included the initiation of cytotoxic chemotherapy, chronic opioid use, pain progression, clinical progression, first subsequent anticancer therapy, and second progression-free survival. There was also more fatigue, hypertension, rash and grade 3-4 fractures, and osteoporosis in the combination therapy arm. It remains to be seen whether this data will be enough to push forward a regulatory approval for this combination. However, one point of interest is that the PSA decline endpoints were in favor of the combination arm. Although the RECIST 1.1 response rates were not presented, a substantial portion of the population in the trial did harbor soft tissue metastases. Hence, in my opinion, the combination could be of clinical utility if response rates are superior for the combination, especially if a patient harbors symptomatic visceral metastasis or pelvic nodal metastasis that is causing or has near potential to cause hydronephrosis and impair kidney function.

Although survival advantage of moving abiraterone acetate earlier in the treatment paradigm has been proven, we have yet to be successful in demonstrating convincing benefit with combination therapy that pairs with abiraterone acetate. The above points towards some early hints of rational combinations, but either data has yet to mature, additional studies must be performed, and/or regulatory agencies must chime in to determine the ultimate fate of these therapeutic combinations. In the meantime, there are still many ongoing trials evaluating novel combinations with abiraterone acetate, and we should continue to actively accrue to the below trials until the patient benefit of a combination is indisputable and the standard of care is definitively altered.

Select combination therapy trials with abiraterone acetate currently open for accrual for mCRPC patients

  1. Randomized phase 2 trial of abiraterone acetate +/-fuzuloparib (NCT04691804)
  2. Phase 1b/2a trial of PLX2853 with abiraterone acetate (NCT04556617)
  3. Phase1/2 trial of abiraterone acetate with Tildrakizumab (NCT04458311)
  4. Phase 1/2 trial of abiraterone acetate with Tazemetostat (NCT04179864)
  5. Abiraterone with SHR3162 (NCT04108247)
  6. Randomized phase 3 (MAGNITUDE) trial of abiraterone acetate with or without niraparib (NCT03748641)
  7. Phase 1 trial of abiraterone with KPG-121 (NCT03569280)
  8. Phase 1/2 of abiraterone with niraparib (QUEST) (NCT03431350)
  9. Randomized phase 2 (CHAARTED2) trial of abiraterone with or without cabazitaxel (NCT03419234)
  10. Randomized phase 2 trial of abiraterone, Olaparib, or abiraterone plus Olaparib for mCRPC patients with DNA repair defects (NCT03012321)
  11. Phase 2 trial of abiraterone with niclosamide (NCT02807805)
Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington

References:

  1. Fizazi K, et al. "Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer." New England Journal of Medicine. 2017. 377:352-60.
  2. James N, et al. "Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy." New England Journal of Medicine. 2017; 377:338-51.
  3. De Bono J, et al. "Abiraterone and Increased Survival in Metastatic Prostate Cancer." New England Journal of Medicine. 2011; 364:1995-2005.
  4. Ryan CJ, et al. "Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy." New England Journal of Medicine. 2013; 368:138-48.
  5. Small EJ, et al. "A Randomized Phase II Trial of Sipuleucel-T with Concurrent versus Sequential Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer." Clinical Cancer Research. 2015; 21:3862-9.
  6. Morris MJ, et al. "Alliance A031201: A phase III trial of enzalutamide (ENZ) versus enzalutamide, abiraterone, and prednisone (ENZ/AAP) for metastatic castration resistant prostate cancer (mCRPC)." Journal of Clinical Oncology. 37, no. 15_suppl (May 20, 2019) 5008-5008.
  7. Smith M, Parker C, Saad F, et al. "Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial." Lancet Oncology. 2019; 20: 408–19.
  8. Slovin S, et al. "Abiraterone acetate (AA) with or without cabazitaxel (CBZ) in treatment of chemotherapy naive metastatic castration-resistant prostate cancer (mCRPC)." Journal of Clinical Oncology. 38, no. 6_suppl (February 20, 2020) 84-84.
  9. De Bono J, et al. "IPATential150: Phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC)." Annals of Oncology. 2020; 31 (suppl_4):S1142-S1215, LBA4.
  10. Shi Z, et al. "Biomarker analysis of the phase III IPATential150 trial of first-line ipatasertib (Ipat) plus abiraterone (Abi) in metastatic castration-resistant prostate cancer (mCRPC)." Journal of Clinical Oncology. 38, no. 6_suppl (February 20, 2020) 182-182.
  11. Yu EY. "PI3K/AKT/mTOR Inhibitors for Prostate Cancer – Finally Hints of a Breakthrough." Urotoday Clinical Trials Portal. On-line: January 5, 2021.
  12. Clarke N, et al. "Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial." Lancet Oncology. 2018; 19:975-86.
  13. Yu EY. "What’s the Rationale for Adding PARP Inhibitors to Androgen Pathway Inhibitors for Patients with Prostate Cancer?" Urotoday Clinical Trials Portal. On-line: October 1, 2020.
  14. Rathkopf DE, et al. "Final results from ACIS, a randomized, placebo (PBO)-controlled double-blind phase 3 study of apalutamide (APA) and abiraterone acetate plus prednisone (AAP) versus AAP in patients (pts) with chemo-naive metastatic castration-resistant prostate cancer (mCRPC)." Journal of Clinical Oncology. 39, no. 6_suppl (February 20, 2021) 9-9.